Lysosomal storage diseases known as mucopolysaccharidoses (MPS) (Klock et al., Internat Pediatr. 9:40-48 (1994); Starr et al., Glycosylation & Disease 1:165-176 (1994)) are caused by a deficiency in an enzyme or combination of enzymes. These lysosomal storage diseases are characterized by intralysosomal accumulation of undegraded glycosaminoglycans, excessive urinary excretion of glycosaminoglycans, progressive mental and physical deterioration, and premature death. Patients are usually born without the visible clinical features of MPS, but develop progressive clinical involvement. Each type of MPS has specific lysosomal enzyme deficiency with a characteristic degree of organ involvement and rate of deterioration. See Muenzer, Adv. Pediatri. 33:269-302 (1986).
For example, MPS VI (Maroteaux-Lamy syndrome) is a lysosomal storage disease in which the affected patients lack the enzyme N-acetylgalactosamine-4-sulfatase (ASB). The enzyme metabolizes the sulfate moiety of glycosaminoglycan (GAG) dermatan sulfate (Neufeld et al., “The mucopolysaccharidoses” The Metabolic Basis of Inherited Disease, Eds. Scriver et al., New York:McGraw-Hill, 1989, pp. 1565-1587). In the absence of the enzyme, the stepwise degradation of dermatan sulfate is blocked and the substrate accumulates intracellularly in the lysosome in a wide range of tissues. The accumulation causes a progressive disorder with multiple organ and tissue involvement in which the infant appears normal at birth, but usually dies before puberty. The diagnosis of MPS VI is usually made at 6-24 months of age when children show progressive deceleration of growth, enlarged liver and spleen, skeletal deformities, coarse facial features, upper airway obstruction, and joint deformities. Progressive clouding of the cornea, communicating hydrocephalus, or heart disease may develop in MPS VI children. Death usually results from respiratory infection or cardiac disease. MPS VI is not typically associated with progressive impairment of mental status, although physical limitations may impact learning and development. Although most MPS VI patients have the severe form of the disease which is usually fatal by the teenage years, affected patients with a less severe form of the disease have been described who may survive for decades.
Some patients die from disease-related complications between childhood and early adulthood. One way to treat lysosomal storage diseases is by intravenous enzyme replacement therapy (ERT) (Kakkis, Expert Opin Investig Drugs 11(5):675-85 (2002)). ERT takes advantage of the vasculature to carry enzyme from a single site of administration to most tissues. Once the enzyme has been widely distributed, it must be taken up into cells. The basis for uptake into cells is found in a unique feature of lysosomal enzymes: lysosomal enzymes constitute a separate class of glycoproteins defined by phosphate at the 6-position of terminal mannose residues. Mannose 6-phosphate is bound with high affinity and specificity by a receptor found on the surface of most cells (Munier-Lehmann et al., Biochem. Soc. Trans. 24(1): 133-6 (1996); Marnell et al., J. Cell. Biol. 99(6):1907-16 (1984)). The mannose 6-phosphate receptor (MPR) directs uptake of enzyme from blood to tissue and then mediates intracellular routing to the lysosome.
Recombinant human ASB (rhASB) has been developed as an enzyme replacement therapy for the treatment of MPS VI. RhASB is internalized into the lysosome through the Calcium Independent Mannose-6-Phosphate Receptor (CIMPR). In this subcellular compartment, the low pH (pH 4-4.5) and proteolysis would decrease or eliminate the interaction of antibody and rhASB.
A potential side effect of administration of enzyme replacement therapy (ERT) is the development of enzyme-specific antibodies in patients receiving multiple rounds of therapy. These enzyme-specific antibodies may precipitate potential adverse events and changes in clinical efficacy, including anaphylactoid-type reactions associated with antibodies of the IgE isotype, changes in pharmacokinetic profile, neutralization of the enzymatic activity in the lysosome, interference with receptor-mediated enzyme uptake, and breaking of tolerance toward self proteins. Reliable assays to accurately measure development of anti-enzyme antibodies would enable assessment of the treatment regimen in a patient receiving ERT and facilitate more efficient design of patient therapy (Mire-Sluis et al., J. Immunological Methods 289:1-16 (2004)). Thus, there remains a need in the art for reliable, sensitive assays that detect antibodies to lysosomal enzymes useful in enzyme replacement therapy.